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Purpose: Intrahepatic cholangiocarcinoma is a fatal primary liver cancer resulting from diagnosis at an advanced stage. Understanding the mechanisms of drug resistance and metastasis of cholangiocarcinoma may improve the disease prognosis. Enhanced aldehyde dehydrogenase (ALDH) activity is suggested to be associated with increased drug resistance and the metastasis. This study aims to investigate the roles of the ALDH isoforms in cholangiocarcinoma., Experimental Design: Aldefluor assays, RT-PCR, and Western blot analysis were used to identify the major ALDH isoforms contributing to Aldefluor activity in human cholangiocarcinoma cell lines. We manipulated isoform expression in HuCCT1 cells to elucidate the role of ALDH1A3 in the malignant progression of these cells. Finally, we used immunohistochemical staining to evaluate the clinical significance of ALDH1A3 in 77 hepatectomized cholangiocarcinoma patients and an additional 31 patients with advanced cholangiocarcinoma who received gemcitabine-based therapy., Results: ALDH(high) cholangiocarcinoma cells not only migrated faster but were more resistant to gemcitabine. Among the 19 ALDH isoforms studied, ALDH1A3 was found to be the main contributor to Aldefluor activity. In addition, we also found that knockdown of ALDH1A3 expression in HuCCT1 cells markedly reduced not only their sensitivity to gemcitabine, which might be attributed to a decreased expression of ribonucleotide reductase M1, but also their migration. Most importantly, this enzyme was also identified as an independent poor prognostic factor for patients with intrahepatic cholangiocarcinoma, as well as a prognostic biomarker of gemcitabine-treated patients., Conclusions: ALDH1A3 plays an important role in enhancing malignant behavior of cholangiocarcinoma and serves as a new therapeutic target. Clin Cancer Res; 22(16); 4225-35. ©2016 AACR., (©2016 American Association for Cancer Research.)

Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA.

Background/aims: To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) compared to radiotherapy (RT) for unresectable, locally advanced hilar cholangiocarcinoma (HCCA)., Methodology: Between 2001 and 2010, 34 patients with unresectable locally advanced HCCA at our institute were reviewed. Eighteen patients received RT and 16 patients received CCRT. Survivals and multivariate analyses were performed to explore potential variables affecting survivals., Results: There were 18 males and 16 females, with a median age of 72 years and median follow-up time 9.4 months. The median overall survival (OS) was 10.4 months (95% CI, 6.7-13.5) with the 1-year survival rates of 41%. The median OS and progression-free survival (PFS) were 13.5 months and 8.8 months for patients receiving CCRT as compared to 6.7 months and 4.4 months for patients receiving RT alone (p = 0.003 and p = 0.005, respectively). On multivariate analysis demonstrated that Karnofsky performance status (KPS) ≥ 80 (p = 0.001), pretreatment carbohydrate antigen 19-9 (CA 19-9) 200 U/ml (p = 0.045) and CCRT were prognostic factors for OS and PFS., Conclusions: As compared with RT, CCRT provides longer OS and PFS for patients with unresectable HCCA. The efficacy of adding novel chemotherapeutic to RT needs to be further investigated.

The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.

Background: Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified., Methods: The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat-shock protein 90 (HSP90) inhibitors with therapeutic potentials., Results: Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit α/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen-activated protein kinase (KRAS/MAPK) pathway., Conclusions: Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA., (Copyright © 2012 American Cancer Society.)

Intrahepatic cholangiocarcinoma (IH-CCA) is the second predominant hepatic malignancy worldwide. However, effective treatment strategies for IH-CCA have not yet been developed. Nab-paclitaxel may be an effective drug against IH-CCA, a type of desmoid-like tumor, and its antitumor effects may be attributable to its ability to disrupt the cancer-associated fibroblasts. In the present study, MTT and Annexin-V apoptosis detection kits were used to evaluate the efficacy of paclitaxel and nab-paclitaxel against human cholangiocarcinoma KKU-100 and KKU-213 cell lines. A rat model of thioacetamide-induced spontaneous desmoplastic IH-CCA was used to compare the treatment response of four different drug regimens: Control, paclitaxel, nab-paclitaxel and gemcitabine/oxaliplatin. Positron emission tomography and immunofluorescence analysis were used to measure the tumor volume and to study the resected tumor, respectively. In vitro, paclitaxel and nab-paclitaxel induced anti-proliferative effects in KKU-100 and KKU-M213 cells. With regards to the treatment regimes, only nab-paclitaxel and gemcitabine/oxaliplatin induced antitumor effects in the rat model of thioacetamide-induced IH-CCA. The immunofluorescence study indicated that nab-paclitaxel was more efficient in disrupting cancer-associated fibroblasts than paclitaxel. In conclusion, nab-paclitaxel is effective against IH-CCA owing to its ability to markedly disrupt the desmoplastic stroma. [ABSTRACT FROM AUTHOR]